Lewis acid mediated vinyl-transfer reaction of alkynes to N-alkylimines by using the N-alkyl residue as a sacrificial hydrogen donor

Article abstract of DOI:10.1002/chem.201300469

A variety of N-alkyl-α,α-dichloroaldimines were vinylated by terminal acetylenes in the presence of Lewis acids such as In(OTf)₃ or BF₃ ?OEt₂ and hexafluoroisopropanol (HFIP) as an additive. The reaction proceeds at ambient temperature and leads to geometrically pure allylic β,β-dichloroamines. This approach is complementary to previously reported transition-metal-catalyzed vinyl-transfer methods, which are not applicable to aliphatic imines and are restricted to imines that contain an electron-withdrawing nitrogen substituent. In the present approach, terminal alkynes were used as a source of the vinyl residue, and the N-alkyl moiety of the imine acts as a sacrificial hydrogen donor. The additional advantage of this methodology is the fact that no external toxic or hazardous reducing agents or molecular hydrogen has to be used. This new methodology nicely combines a C(sp²))-C(sp) bond formation, hydride transfer, and an unusual cleavage of an unactivated C-N bond, thereby giving rise to functionalized primary allylic amines. A detailed experimental study supported by DFT calculations of the mechanism has been done.

Full text of DOI:10.1002/chem.201300469

FULL PAPER
DOI: 10.1002/chem.201300469
Lewis Acid Mediated Vinyl-Transfer Reaction of Alkynes to N-Alkylimines
by Using the N-Alkyl Residue as a Sacrificial Hydrogen Donor
Chandi C. Malakar,[a] Sara Stas,[b] Wouter Herrebout,[c] and
Kourosch Abbaspour Tehrani*[a]
Dedicated to Professor Norbert De Kimpe on the occasion of his 65th birthday
Abstract: A variety of N-alkyl-a,a-di-
chloroaldimines were vinylated by ter-
minal acetylenes in the presence of
to aliphatic imines and are restricted to
imines that contain an electron-with-
drawing nitrogen substituent. In the
present approach, terminal alkynes
were used as a source of the vinyl resi-
due, and the N-alkyl moiety of the
imine acts as a sacrificial hydrogen
donor. The additional advantage of this
methodology is the fact that no exter-
nal toxic or hazardous reducing agents
or molecular hydrogen has to be used.
This new methodology nicely combines
Lewis acids such as InACTHNUTRGNEUNG(OTf)3 or
BF3·OEt2 and hexafluoroisopropanol
(HFIP) as an additive. The reaction
proceeds at ambient temperature and
leads to geometrically pure allylic b,b-
dichloroamines. This approach is com-
plementary to previously reported
2
À
a C
G
dride transfer, and an unusual cleavage
À
of an unactivated C N bond, thereby
giving rise to functionalized primary al-
lylic amines. A detailed experimental
study supported by DFT calculations
of the mechanism has been done.
Keywords: alkynes
·
amines
·
imines · Lewis acids · redox chemis-
try
ACHTUNGTRENNUNGtransition-metal-catalyzed vinyl-trans-
fer methods, which are not applicable
Introduction
enantioselective addition of vinylzinc reagents;[4f–g,7] these
can be introduced in two steps, which involves in situ alkyne
hydroboration and transmetalation of boron against zinc,
applying ZnMe2 to the corresponding imines. To serve this
purpose, a broad range of enantioselective catalysts includ-
ing both early-transition-metal catalysts (Hf, Ti, Zr) and
late-transition-metal catalysts (Cu, Rh) have been employ-
ed.[4f] Apart from the drawbacks with regard to the in situ
generation of the corresponding vinylzinc reagents, it is
worth mentioning that the enantioselective addition of vinyl-
zinc to imines is restricted to the activated N-acyl- and N-
(diphenylphosphinoyl)imines.[6] Further advances on the
synthesis of allylic amines, namely, the catalytic enantiose-
lective addition of organoboron,[4f] organolithium, organotin,
and organotitanium reagents to imines, employ several
metal catalysts including rhodium catalysts.[4g,h] The develop-
ment of transition-metal-catalyzed reductive coupling be-
tween imines and alkynes could bypass the use of organo-
metallic reagents. Because these protocols need a terminal
reductant such as hydrosilanes, hydrostannanes, organozinc
reagents, organoboron reagents, or chromium(II) chloride,
the formation of equimolar amounts of hazardous byprod-
ucts is still a point of concern.[4,6,7]
Allylic amines are highly appreciated precursors in modern
synthetic organic chemistry owing to their extensive use in
the synthesis of therapeutic agents and bioactive natural
products.[1] Moreover, their preparation as well as utilization
in enantiomerically enriched forms has gained considerable
awareness in recent years.[1,2] Although the vinylation of al-
dehydes and ketones to produce the corresponding allylic al-
cohols has been thoroughly devised,[3] the corresponding
imine vinylation acknowledges a supplementary demand in
organic synthesis.[1,4] In addition to the well-documented en-
tries based on transition-metal-catalyzed allylic substitution
by N-nucleophiles,[2b,c,e,f,5]
a surrogate avenue to allylic
amines based on the influential development of Soai et al.[6g]
relied on the catalytic enantioselective vinylation of
imines.[1,2,4,7] The latter case generally involves the catalytic
[a] Dr. C. C. Malakar, Prof. Dr. ir. K. Abbaspour Tehrani
Organic Synthesis, Faculty of Sciences, University of Antwerp
Groenenborgerlaan 171, 2020 Antwerp (Belgium)
Fax : (+32)3-265-32-33
E-mail: Kourosch.AbbaspourTehrani@uantwerpen.be
[b] Dr. S. Stas
In this respect, progress has been made by Krische et al.
by using molecular hydrogen as the cleanest and most cost-
effective reducing agent for the catalytic enantioselective re-
ductive alkyne–imine coupling.[4,8] Because most of the pre-
viously reported methods rely on either organometallic re-
agents as the source of the vinylic moiety or on hazardous
reducing agents, the development of an efficient and mild
Laboratory of Organic Chemistry, Vrije Universiteit Brussel
Pleinlaan 2, 1050 Brussels (Belgium)
[c] Prof. Dr. W. Herrebout
Cryospectroscopy, University of Antwerp
Groenenborgerlaan 171, 2020 Antwerp (Belgium)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300469.
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!

phenyl-N-propylpent-1-yn-3-amine (4a) in 16% yield, an
unknown, albeit vinylated compound was also observed in
20% yield (yield calculated by 1H NMR spectroscopy;
Table 1, entry 1). After careful flash chromatography and
structural elucidation, this compound was identified as (E)-
4,4-dichloro-1-phenylpent-1-en-3-amine (3a).
Table 1. Preliminary screening of the reaction conditions for the synthe-
sis of 3a.[a]
Entry
Lewis acid/
[mol%]
T [8C]
Yield[b] [%]
20[c]
37
36
29
72
56
41
16
Scheme 1. Summary of reported work and this work.
1
2
3
4
5
6
7
8
FeCl3/25
CuCl2/100
50
RT
RT
RT
RT
RT
50
Cu
AgOTf/100
In(OTf)3/100
Sc(OTf)3/100
ACHTUNGRTENN(UNG OTf)2/100
protocol for the synthesis of allylic amines from alkynes and
imines remains a challenging mission (Scheme 1). Basically,
the envisioned conversion is characterized by an internal
redox isomerization. Mechanistically, this process involves a
[1,5]-hydride shift, catalyzed by Lewis or Brønsted acids,
which have attracted much attention lately.[9] Herein, we
would like to report on the synthesis of geometrically pure
allylic b,b-dichloroamines by using a Lewis acid promoted
reaction between a,a-dichloroaldimines and terminal al-
kynes. The reaction mechanism and feasibility of the vinyla-
tion process was supported by quantum mechanical calcula-
tions. In this method, reductive vinylation of the imine by al-
kynes is accomplished by hydrogen transfer from the N-
alkyl residue. In addition to the novelty of the described re-
action, this important class of electrophiles is not commonly
studied, so conceivably there is a certain novelty to these re-
actions.[10a] In this context special reference should be made
with regard to the chelation-controlled addition of in situ
generated vinylzinc reagents to a N-tosyl-a-chloroaldimi-
ne.[6h] To the best of our knowledge, there is no report of a
vinyl-transfer reaction that relies on a sacrificial N-alkyl res-
idue that is responsible for the selective intramolecular re-
duction of alkyne to the corresponding E alkene. In addi-
tion, vinyl-transfer reactions that use aliphatic aldimines
have not been studied (Scheme 1).
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
InCl3/50
ZnCl2/50
50
[a] Unless otherwise mentioned, 0.5 mmol of 1a and 0.5 mmol of 2a were
reacted in a sealed vial. [b] Yields after acid–base workup. [c] Additional-
ly 4,4-dichloro-1-phenyl-N-propylpent-1-yn-3-amine (4a) was observed in
1
the H NMR spectra.
Since it has been proven[11] that fluorinated alcohols can
have magnificent effects on the efficiency, regioselectivity,
and stereoselectivity of several chemical transformations,
further screening of the reaction conditions in CH2Cl2 was
performed using metal salts such as CuCl2, CuACTHNUTRGNE(NUG OTf)2, and
AgOTf in the presence of 1,1,1,3,3,3-hexafluoro-2-propanol
(HFIP) as an additive. We were gratified to observe that the
yield of the desired product 3a was increased to 37%
(Table 1, entries 2–4) without the identifiable formation of
any side products. Interestingly, the introduction of Lewis
acids such as InACHTNUTRGENNUG(OTf)3 and ScACHTUNGTREN(NNGU OTf)3 in the presence of
HFIP as an additive afforded (E)-4,4-dichloro-1-phenylpent-
1-en-3-amine (3a) in good to high yields (Table 1, entries 5
and 6). Although InCl3 and ZnCl2 as Lewis acids were also
able to accomplish the desired transformation, the yields of
the allylic amine 3a remained relatively low (Table 1, en-
tries 7 and 8).
Results and Discussion
Next, this transformation was studied in further detail to
find more optimal conditions (Table 2). Interestingly, it was
observed that by decreasing the amount of InACTHGUNETRNNU(G OTf)3 to
50 mol%, product 3a was isolated in 65% yield when the
reaction was conducted at ambient temperature, whereas
product 3a was formed in 53% yield by performing the re-
action at 508C (Table 2, entries 1 and 2). Notably, by substi-
tuting dichloromethane for toluene as a solvent, the yield of
3a dropped dramatically (Table 2, entries 3 and 4). Further
On the basis of our recent contribution[10b] on the synthesis
of a new class of polychlorinated propargylic amines by
using an indiumACHTUNGTRENNUNG(III)-catalyzed reaction between a,a-dichlor-
oaldimines and terminal alkynes, our interest shifted to
vinyl-transfer reactions, because the related polychlorinated
allylic amines are also rarely studied structural moieties in
modern organic synthesis. During the screening of the reac-
tion conditions for the alkynylation of N-(2,2-dichloro-1-pro-
pylidene)amine (1a) with phenylacetylene (2a) in the pres-
ence of 25 mol% FeCl3 as catalyst and dichloromethane as
solvent, in addition to the formation of 4,4-dichloro-1-
attempts using 25 and 10 mol% of InACTHNUTRGNEUNG(OTf)3 (Table 2, en-
tries 5–7) and decreasing the reaction times (Table 2,
entry 8) as well as the amounts of HFIP (Table 2, entry 9)
only led to lower yields of 3a. Moreover, it was found that
&
2
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Vinyl-Transfer Reaction
FULL PAPER
Table 2. Optimization of the reaction conditions for the synthesis of 3a.[a]
electron-donating (Table 3, entries 1–7) and electron-with-
drawing substituents (Table 3, entries 8–10) were tolerated
under the reaction conditions and produced the correspond-
ing product 3 in yields that ranged from 53 to 78%
(Table 3).
The scope of the arylacetylene was also evaluated. A
broad range of electron-donating groups such as methyl,
ethyl, tert-butyl, and methoxy groups, and an electron-with-
drawing group such as a fluoro group (in the presence of
methyl group) on the benzene ring survived under the reac-
tion conditions and produced 4,4-dichloro-1-arylpent-1-en-3-
amines 3 in yields that ranged from 53 to 66% (Table 4).
Entry
In
E
(OTf)3
Solvent
(3.6 mL)
Additive
T
[8C]
Yield[b]
[%]
N
1
2
3
4
5
6
7
8
9
50
50
50
50
25
25
10
50
50
50
50
CH2Cl2
CH2Cl2
PhCH3
PhCH3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
HFIP (0.4 mL)
HFIP (0.4 mL)
HFIP (0.4 mL)
HFIP (0.4 mL)
HFIP (0.4 mL)
HFIP (0.4 mL)
HFIP (0.4 mL)
HFIP (0.4 mL)
HFIP (1 mmol)
tBuOH (1 mmol)
TFA (1 mmol)
50
53
65
38
35
41
33
27
34[c]
43
7[d]
0
RT
RT
50
RT
50
50
RT
RT
RT
RT
Table 4. InACHTNUTRGNE(UNG OTf)3-mediated reaction between 1a and various arylacety-
10
11
lenes 2.[a]
[a] Unless otherwise mentioned, 0.5 mmol of 1a and 0.5 mmol of 2a were
reacted in a sealed vial. [b] Yields after acid–base workup. [c] Reaction
was carried out for 12 h. [d] Additionally, 4,4-dichloro-1-phenyl-N-propyl-
1
pent-1-yn-3-amine (4a) was observed in the H NMR spectra.
Entry
2
Ar
Product 3
Yield 3 [%][b]
1
2
3
4
5
6
b
c
d
e
f
4-MeC6H4
4-EtC6H4
4-tBuC6H4
3-MeOC6H4
4-BrC6H4
e
f
g
h
i
65
53
66
tBuOH as an additive was much less effective (Table 2,
entry 10) as only 7% of the vinylated product 3a was ob-
served in the H NMR spectra in addition to 69% of 4,4-di-
chloro-1-phenyl-N-propylpent-1-yn-3-amine (4a). On the
other hand, the addition of 2 equivalents of trifluoroacetic
acid (TFA) completely inhibited this transformation
(Table 2, entry 11). Taking into account an acceptable yield
1
62
55[c]
61
g
4-F-3-MeC6H3
j
[a] Unless otherwise mentioned, 0.5 mmol of 1a and 0.5 mmol of 2a were
reacted in a sealed vial. [b] Yields after acid–base workup. [c] GC yield.
of 65% of 3a and considering the cost of InACTHNURTGNENG(U OTf)3, the opti-
mal reaction conditions for this conversion were established
when 0.5 mmol of 1a and 0.5 mmol of 2a were reacted in
the presence of 50 mol% of InACHTUNGRTNEUNG(OTf)3 as catalyst in CH2Cl2/
Further extensions of the substrate scope revealed that the
introduction of extra steric hindrance on the a,a-dichloroal-
dimines leads to both vinylation product and alkynylation
product in a 1.3/1 ratio (see the Supporting Information). It
was also found that the presence of strong electron-with-
drawing groups such as chloro and nitro groups in both the
ortho and para position of the arylacetylene completely hin-
dered the formation of the vinylated product and gave rise
to the 4,4-dichloro-1-aryl-N-propylpent-1-yn-3-amines 4 (see
the Supporting Information). Surprisingly, the reaction of 1a
with 4-bromophenylacetylene under the optimized condi-
tions afforded the corresponding allylic b,b-dichloroamine
3g (Table 4, entry 5). The simultaneous presence of a strong
electron-withdrawing fluoro group and an electron-donating
methyl group on the arylacetylene (Table 4, entry 6) or an
electron-donating alkyl group on the arylacetylene (Table 4,
entries 1–3) also promoted the selective formation of the
corresponding vinylated compounds 3.
HFIP (9:1) for 18 h at ambient temperature (Table 2,
entry 2).
With the optimal conditions at hand, the scope of this
transformation was studied (Table 3). It was found that a
broad range of a,a-dichloroaldimines 1 that contain both
Table 3. InACHTUNGTRENNUNG(OTf)3-mediated synthesis of 3 using various a,a-dichloroaldi-
mines 1.[a]
Entry
1
R1
R2
Product 3
Yield 3 [%][b]
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
Me
Me
Me
Me
Me
Et
Et
iPr
Cl3C
Cl3C
Cl3C
nPr
Et
iPr
allyl
Bn
Et
nPr
allyl
nPr
iPr
a
a
a
a
a
b
b
c
65
60
78
54
73
53
59
63[c]
53
58
65
In an attempt to avoid the formation of variable amounts
of alkynylated side products, InACTHNUTRGNENUG(OTf)3 was replaced by a
stronger Lewis acid (Table 5). To our delight, the reaction of
a,a-dichloroaldimine 1a and phenylacetylene in the pres-
ence of 1 equivalent of BF3·OEt2 in CH2Cl2/HFIP (9:1) for
5 h under reflux conditions gave rise to 3a in 40% yield
without any trace of the propargylic amine 4a (Table 5,
entry 1). After a careful screening of the reaction conditions
by using BF3·OEt2 as a Lewis acid (Table 5, entries 1–7), it
d
d
d
10
11
j
k
allyl
[a] Unless otherwise mentioned, 0.5 mmol of 1a and 0.5 mmol of 2a were
reacted in a sealed vial. [b] Yields after acid–base workup. [c] GC yield.
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
&
ÞÞ
These are not the final page numbers!

K. Abbaspour Tehrani et al.
Table 5. Optimization of the reaction conditions for the BF3·OEt2-medi-
ated reaction between 1a and 2a.[a]
Table 7. BF3·OEt2-mediated reaction between 1a and 2.[a]
Entry
Reaction conditions
Solvent/Additive
Yield 3a [%][b]
1
2
3
4
5
6
7
reflux, 5 h
reflux, 2 h
RT, 5 h
RT, 18 h
RT, 5 h
CH2Cl2/HFIP (9:1)
CH2Cl2/HFIP (9:1)
CH2Cl2/HFIP (9:1)
CH2Cl2/HFIP (9:1)
EtOH
40
32
45
62
0
Entry
1
2
Ar
Product 3
Method/Yield 3 [%][b]
b
4-MeC6H4
e
A/63
B/57
A/41
B/23
A/55
B/44
A/53
B/36
2
3
4
c
e
g
4-EtC6H4
f
h
j
reflux, 5 h
reflux, 5 h
CH2Cl2/TFE[c] (9:1)
CH2Cl2/PhOH (9:1)
23
30
3-MeOC6H4
4-F-3-MeC6H3
[a] Unless otherwise mentioned, 0.5 mmol of 1a and 0.5 mmol of 2a were
reacted in a sealed vial. [b] Yields after acid–base workup. [c] 2,2,2-Tri-
fluoroethanol.
[a] Unless otherwise mentioned, 0.5 mmol of 1a and 0.5 mmol of 2 were
reacted in a sealed vial. [b] Yields after acid–base workup.
can be concluded that the reaction between 1a and 2a in
the presence of 1 equiv of BF3·OEt2 as Lewis acid in
CH2Cl2/HFIP (9:1) for 18 h at ambient temperature (meth-
od A) or under reflux conditions for 5 h (method B) afford-
ed the maximum yield of the product 3a (Table 5, entries 1
and 4). These reaction conditions were used to investigate
the scope of the various imines 1 and arylacetylenes 2
(Tables 6 and 7).
nylacetylene (2a) in the presence of 1 equivalent of
BF3·OEt2 in CH2Cl2 under reflux conditions for 5 h
(Scheme 2). After alkaline extraction of the reaction mix-
ture using 0.5m NaOH, H NMR spectroscopic analysis of
the crude mixture showed the presence of 12 mol% of un-
1
Table 6. BF3·OEt2-mediated reaction between 1 and 2a.[a]
Scheme 2. Evidence for the formation of intermediate 5.
Entry
1
1
a
R1
R2
Product 3
Method/Yield 3 [%][b]
Me
nPr
a
A/62
B/40
A/53
B/44
A/55
B/45
A/51
B/30
A/57
B/49
A/49
reacted starting imine 1a, 24 mol% of phenylacetylene (2a),
and 64 mol% of the 2-aza-1,4-diene N-(4,4-dichloropent-1-
en-3-yl)propylidenamine (5). The latter product is readily
hydrolyzed to (E)-4,4-dichloro-1-phenylpent-1-en-3-amine
(3a) after acid–base extraction of the crude reaction mixture
(Scheme 2). When the same reaction was carried out in
CH2Cl2, but now in the presence of the cosolvent HFIP
(9:1), alkaline extraction of the resulting crude mixture gave
2
3
4
5
6
b
c
Me
Me
Me
Me
Et
Et
a
a
a
a
b
iPr
allyl
Bn
d
e
g
1
nPr
rise to a very complicated H NMR spectrum. Again, acid–
[a] Unless otherwise mentioned, 0.5 mmol of 1 and 0.5 mmol of 2a were
reacted in a sealed vial. [b] Yields after acid–base workup.
base extraction afforded the corresponding product 3a.
Next, the addition of 1 equivalent of [D]phenylacetylene
(6) to N-(2,2-dichloro-1-propylidene)propylamine (1a) was
investigated in the presence of 1 equivalent of BF3·OEt2
in CH2Cl2/HFIP (9:1) under reflux conditions for 5 h
(Scheme 3). After acid–base extraction of the crude reaction
To elucidate the mechanistic aspects of this vinylation
process, several experiments were performed. The reaction
of N-tert-butyl-(2,2-dichloro-1-propylidene)amine and phe-
nylacetylene (2a) under reaction conditions B did not lead
to the expected vinylated product, which clearly indicates
that the presence of at least one hydrogen atom on the a’-
carbon atom of N-alkyl residue is mandatory. Moreover, the
formation of propanal as a side product was identified by
GC-MS by performing a reaction between 1 equivalent of
N-(2,2-dichloro-1-propylidene)propylamine (1a) and phe-
Scheme 3. BF3·OEt2-mediated synthesis of 7.
&
4
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Vinyl-Transfer Reaction
FULL PAPER
mixture, the vinylated product 7 was obtained in 39% yield.
Interestingly, the deuterium atom in product 7 was still re-
siding on its original carbon atom. This result clearly ex-
cludes the possibility of the deprotonation of phenylacety-
lene prior to the addition to 1a. On the other hand, when
the same reaction was performed in the presence of
50 mol% of InACHTUNGTRENNUNG(OTf)3 in CH2Cl2/HFIP (9:1) at ambient tem-
perature for 18 h, to some extent (17%) the formation of
1
the nondeuterated 3a was observed in the H NMR spec-
trum. This can be explained by the formation of phenylace-
tylene (2a) from in situ generated indiumacetylides, which
are reprotonated by HFIP during the course of the reaction.
An intramolecular kinetic isotope effect (KIE) study was
conducted with substrate 8. For this, monodeuterated N-
(2,2-dichloro-1-propylidene)propylamine 8 was treated with
phenylacetylene (2a) in the presence of 1 equivalent of
BF3·OEt2 in CH2Cl2/HFIP (9:1) under reflux conditions for
5 h (Scheme 4). After acid–base extraction, a mixture that
Figure 1. Reaction coordinate obtained for the vinylation process involv-
ing N-(2,2-dichloroethylidene)ethanamine and phenylacetylene. The cal-
culations were performed at the B3LYP/TZ2P level, using a self-consis-
tent reaction field (SCRF) model to correct for solvent stabilizations.
The energies for the transition states, the intermediate, and the reaction
products relative to that of the reagents are 88.3, 104.2, 84.6, and
À140.3 kJmolÀ1, respectively.
timizations, and the lowest vibrational frequencies that
prove the nature of the stationary points are summarized in
the Supporting Information.
Scheme 4. Determination of the intramolecular deuterium kinetic isotope
effect.
The stepwise mechanism (Scheme 5) starts with the coor-
dination of BF3·OEt2 or another Lewis acid with the nitro-
gen atom of the a,a-dichlorinated imine 1, as described re-
cently in literature,[14] thus making the imino-carbon atom
more electrophilic. The presence of at least two chloro
consisted of vinylated products 3a and 9 was obtained. The
formation of the deuterated (E)-[D]4,4-dichloro-1-phenyl-
pent-1-en-3-amine-1 (9) proves the migration of the deuteri-
um atom from the a’-carbon atom of the N-alkyl residue to
the C-2 of the phenylacetylene (2a).
Considering the formation of the nondeuterated and deu-
terated addition products 3a and 9 in a 1.3/1.0 ratio (kH/
kD =1.3), one can assume that the breaking of the carbon–
deuterium bond in the starting material 8 is subjected to a
kinetic isotope effect, regardless of mechanism.[12] However,
this does not automatically indicate that the breaking of the
À
C H(D) bond in 1a (8) is involved in the rate-determining
step.[12b]
The proposed stepwise mechanism for the vinylation proc-
ess with phenylacetylene is supported by density functional
theory calculations that involved N-(2,2-dichloroethylide-
ne)ethanamine as the model imine. The calculations were
performed at the B3LYP/TZ2P level of theory using Gaussi-
an 09.[13] Corrections for the solvent, a mixture of dichloro-
methane and HFIP (9:1), were accounted for by using the
standard self-consistent reaction field (SCRF) model. The
equilibrium geometries for the reagents, the reaction prod-
uct, the intermediate, and the transition states involved, and
the reaction coordinates derived are shown schematically in
Figure 1. The Cartesian coordinates for the different geome-
tries, the maximum forces obtained during the geometry op-
Scheme 5. Proposed stepwise mechanism for the BF3·OEt2-mediated syn-
thesis of 3a.
atoms in the a position of the imine function is also essential
to make the azomethine carbon atom in the BF3 complex 10
even more electrophilic. In the stepwise mechanism
(Scheme 5), nucleophilic addition of phenylacetylene (2a)
to the activated imine 10 takes place, thereby resulting in
the formation of an allene-type intermediate 11, which
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!

K. Abbaspour Tehrani et al.
expels a hydride ion by means of a b-hydride elimination
mechanism. Such a mechanism is also known for alkyllithi-
um compounds that contain a b-hydrogen atom, and hence
act as hydride donors.[15] Conceptually related [1,5]-hydride-
transfer reactions, from carbon atoms a to the nitrogen
atom to an electron acceptor, such as an activated vinyl
group,[9d,f,k,l] iminium bond,[9e] imine,[9c,h,i] or aldehyde[9j] have
been reported in the literature.
The calculated dipole moments of the transition states
and intermediate 11 are large and will be strongly stabilized
by the solvent (TS1=16.0 debye, IM=18.8 debye, TS2=
15.96 debye). This probably explains why this reaction only
can proceed in the presence of HFIP. HFIP is a highly polar
solvent and has a bigger dielectric constant (ENT =1.068, e=
16.6) than dichloromethane (ENT =0.309, e=8.9).[16] The in-
termediate carbocation 11 finally undergoes a formal 1,5-hy-
dride shift to form azadiene 5, which after hydrolysis deliv-
ers the final product 3a (Scheme 5). This conversion resem-
bles the Crabbꢁ homologation, which involves the one-pot
preparation of allenes by CuI-catalyzed coupling of alkynes
with formaldehyde by using a sacrificial secondary amine as
a hydride donor.[17] In this process an in situ formed propar-
gylic amine undergoes a 1,5-sigmatropic rearrangement of
hydrogen, thereby giving rise to the allene and an imine. Al-
though similar, this mechanism is not applicable in our case,
since no intermediate propargylic amine is formed. In a con-
trol reaction of 4,4-dichloro-1-phenyl-N-propylpent-1-yn-3-
amine (4a)[10b] with 1 equivalent of BF3·OEt2 in CH2Cl2/
HFIP (9:1) under reflux conditions for 5 h, no reaction was
observed.
Figure 2. Reaction coordinate obtained for the vinylation process involv-
ing N-(2,2-dichloroethylidene)ethanamine and propyne. The calculations
were performed at the B3LYP/TZ2P level, using an SCRF model to cor-
rect for solvent stabilizations. The activation energy for the concerted re-
action equals 129.0 kJmolÀ1
.
To further rationalize the results derived for phenylacety-
lene, DFT calculations were also initiated for the reaction of
N-(2,2-dichloro-1-propylidene)propylamine (1a) with an ali-
phatic alkyne, such as propyne (2h). The equilibrium geo-
metries for the reagents, the reaction product, and the tran-
sition state involved, and the reaction coordinate that sug-
gests a concerted one-step mechanism are shown schemati-
cally in Figure 2. As before, the details for the geometries
obtained are given in the Supporting Information. The acti-
vation energy for the concerted process equals
129.0 kJmolÀ1, which is much higher than the values of 88
(TS1) and 104 kJmolÀ1 (TS2) found for the same reaction of
1a with phenylacetylene. Of course, in the case of the reac-
tion of 1a with propyne, no stabilized allene type of inter-
mediate is formed, which explains the one-step character of
this conversion (Scheme 6).
Scheme 6. Proposed concerted mechanism for the BF3·OEt2-mediated
synthesis of 3k.
Scheme 7. BF3·OEt2-mediated reaction between 1a and alkylacetylenes
2i,j.
On the basis of this prediction, we decided to investigate
the reaction of N-(2,2-dichloro-1-propylidene)propylamine
(1a) with 1-hexyne and cyclohexylacetylene in the presence
of BF3·OEt2 in CH2Cl2/HFIP (9:1). No reaction was ob-
served at all when these reactions were performed at room
temperature. However, by heating the reaction mixture in
sealed vials at 508C, the allylic b,b-dichloroamines 3l and
3m were obtained in 61 and 75% yield, respectively
(Scheme 7).
energy calculated for the concerted process. It is worth men-
tioning that when the same reactions were carried out in the
presence of InACHTNUTRGNEUNG(OTf)3 at room temperature or even at 508C,
no vinylated products were formed. Instead, the correspond-
ing propargylic b,b-dichloroamines 4l and 4m were isolated
in 82 and 86% yield, respectively (see the Supporting Infor-
mation).
The higher temperature required for the conversion of ali-
phatic alkynes is in accordance with the higher activation
&
6
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Vinyl-Transfer Reaction
FULL PAPER
Kong, M. J. Krische, J. Am. Chem. Soc. 2007, 129, 7242–7243;
d) M.-Y. Ngai, A. Barchuk, M. J. Krische, J. Am. Chem. Soc. 2007,
129, 12644–12645; e) J. R. Kong, C.-W. Cho, M. J. Krische, J. Am.
Chem. Soc. 2005, 127, 11269–11276; f) S. J. Patel, T. F. Jamison,
Angew. Chem. 2003, 115, 1402–1405; Angew. Chem. Int. Ed. 2003,
42, 1364–1367; for recent reviews, see: g) J. F. Bower, M. J. Krische,
Top. Organomet. Chem. 2011, 34, 107–138; h) R. L. Patman, J. F.;
Bower, I. S. Kim, M. J. Krische, Aldrichimica Acta 2008, 41, 95–104.
[5] a) G. Helmchen, in Iridium Complexes in Organic Synthesis (Eds.:
L. A. Oro, C. Claver), Wiley-VCH, Weinheim, 2009, p. 211; b) L.
Acemoglu, J. M. J. Williams, in Handbook of Organopalladium
Chemistry for Organic Synthesis, Vol. 1 and 2 (Eds.: E. Negishi, A.
de Meijere, Wiley, New York, 2002, p. 1689; for reviews, see: c) Z.
Lu, S. Ma, Angew. Chem. 2008, 120, 264–303; Angew. Chem. Int.
Ed. 2008, 47, 258–297; d) G. Helmchen, A. Dahnz, P. Dꢄbon, M.
Schelwies, R. Weihofen, Chem. Commun. 2007, 675–691.
[6] a) I. Sato, K. Hosoi, R. Kodaka, K. Soai, Eur. J. Org. Chem. 2002,
3115–3118; b) X. Zhang, W. Lin, L. Gong, A. Mi, X. Cui, Y. Jiang,
M. C. K. Choi, A. S. C. Chan, Tetrahedron Lett. 2002, 43, 1535–1537;
c) C. Jimeno, S. Reddy, L. Sola, A. Moyano, M. A. Pericas, A.
Riera, Org. Lett. 2000, 2, 3157–3159; d) P. Brandt, C. Hedberg, K.
Lawonn, P. Pinho, P. G. Andersson, Chem. Eur. J. 1999, 5, 1692–
1699; e) D. Guijarro, P. Pinho, P. G. Andersson, J. Org. Chem. 1998,
63, 2530–2535; f) P. G. Andersson, D. Guijarro, D. Tanner, J. Org.
Chem. 1997, 62, 7364–7375; g) K. Soai, T. Hatanaka, T. Miyazawa,
J. Chem. Soc. Chem. Commun. 1992, 1097–1098; h) G. R. Stanton,
P.-O. Norrby, P. J. Carroll, P. J. Walsh, J. Am. Chem. Soc. 2012, 134,
17599–17604.
Conclusion
In conclusion, various N-alkyl-a,a-dichloroaldimines were
successfully vinylated by using a wide variety of terminal al-
kynes as the vinyl source in the presence of Lewis acids
such as InACHTUNGTRENNUNG(OTf)3 and BF3·OEt2. The allylic b,b-dichloroa-
mines, all with E configurations, formed in this conversion
could be easily isolated in pure form by simple acid–base ex-
traction. This transformation can only proceed in the pres-
ence of HFIP, and uses the N-alkyl residue of the imine as a
reducing equivalent, which ultimately leads to its removal
from the nitrogen atom of the allylic amine. The mechanism
of this unprecedented vinyl-transfer reaction was investigat-
ed by a detailed experimental study and is supported by
DFT calculations. For arylacetylenes a stepwise reaction
path is followed, whereas aliphatic terminal acetylenes react
in a concerted fashion. In both mechanisms a 1,5-hydride
shift from the N-alkyl moiety of the imine to the alkyne
holds a central place.
Acknowledgements
This work was financially supported by the University of Antwerp (man-
date CCM) and the Research Foundation Flanders (mandate SS). Finan-
cial support through the Flemish Government and the Hercules Founda-
tion that allowed the purchase of the CalcUA supercomputing clusters is
acknowledged. We are also thankful to Ing. Heidi Seykens, Prof. Dr.
Filip Lemiere, and Ing. Norbert Hanckꢁ for recording NMR spectra and
HRMS analyses.
[7] For reviews, see: a) K.-I. Yamada, K. Tomioka, Chem. Rev. 2008,
108, 2874–2886; b) F. Schmidt, R. T. Stemmler, J. Rudolph, C.
Bolm, Chem. Soc. Rev. 2006, 35, 454–470; c) T. Vilaivan, W. Bhan-
thumnavin, Y. Sritana-Anant, Curr. Org. Chem. 2005, 9, 1315–1392;
d) S. Kobayashi, H. Ishitani, Chem. Rev. 1999, 99, 1069–1094; e) R.
Bloch, Chem. Rev. 1998, 98, 1407–1438.
[8] a) V. Farina, J. T. Reeves, C. H. Senanayake, J. J. Song, Chem. Rev.
2006, 106, 2734–2793; b) C. Jꢅkel, R. Paciello, Chem. Rev. 2006,
106, 2912–2942; c) Asymmetric Catalysis on Industrial Scale (Eds.:
H. U. Blaser, E. Schmidt), Wiley-VCH, Weinheim, 2004; d) Hetero-
geneous Catalysis and Fine Chemicals IV (Eds.: H. U. Blaser, A.
Baiker, R. Prins), Elsevier, Amsterdam, 1997.
[1] For reviews, see: a) M. Johannsen, K. A. Jørgensen, Chem. Rev.
1998, 98, 1689–1708; b) R. B. Cheikh, R. Chaabouni, A. Laurent, P.
Mison, A. Nafti, Synthesis 1983, 685–700.
[2] For reviews, see: a) E. M. Skoda, G. C. Davis, P. Wipf, Org. Process
Res. Dev. 2012, 16, 26–34; b) R. Takeuchi, S. Kezuka, Synthesis
2006, 3349–3366; c) H. Miyabe, Y. Takemoto, Synlett 2005, 1641–
1655; d) L. E. Overman, N. E. Carpenter, Org. React. 2005, 66, 1–
107; e) B. M. Trost, J. Org. Chem. 2004, 69, 5813–5837; f) B. M.
Trost, M. L. Crawley, Chem. Rev. 2003, 103, 2921–2943; for selected
examples, see: g) S. J. Patel, T. F. Jamison, Angew. Chem. 2004, 116,
4031–4034; Angew. Chem. Int. Ed. 2004, 43, 3941–3944; h) P. Wipf,
C. Kendall, C. R. J. Stephenson, J. Am. Chem. Soc. 2003, 125, 761–
768; i) R. B. Grossman, W. M. Davis, S. L. Buchwald, J. Am. Chem.
Soc. 1991, 113, 2321–2322; j) T. Ohmura, J. F. Hartwig, J. Am.
Chem. Soc. 2002, 124, 15164–15165.
[3] For reviews, see: a) M. Hatano, K. Ishihara, Chem. Rec. 2008, 8,
143–155; b) J. Montgomery, G. J. Sormunen, Top. Curr. Chem. 2007,
279, 1–24; c) D. J. Ramꢂn, M. Yus, Chem. Rev. 2006, 106, 2126–
2208; d) C. Garcꢃa, V. S. Martin, Curr. Org. Chem. 2006, 10, 1849–
1889; e) D. J. Ramꢂn, M. Yus, Angew. Chem. 2004, 116, 286–289;
Angew. Chem. Int. Ed. 2004, 43, 284–287; f) P. Wipf, R. L. Nunes,
Tetrahedron 2004, 60, 1269–1279; g) P. Wipf, C. Kendall, Chem. Eur.
J. 2002, 8, 1778–1784; h) L. Pu, H.-B. Yu, Chem. Rev. 2001, 101,
757–824; for selected examples, see: i) M.-Y. Ngai, A. Barchuk,
M. J. Krische, J. Am. Chem. Soc. 2007, 129, 280–281; j) H. Li, P. J.
Walsh, J. Am. Chem. Soc. 2005, 127, 8355–8361; k) S.-J. Jeon, H. Li,
C. Garcia, L. K. La Rochelle, P. J. Walsh, J. Org. Chem. 2005, 70,
448–455; l) H. Li, P. J. Walsh, J. Am. Chem. Soc. 2004, 126, 6538–
6539.
[9] For a review see: a) E. A. Mitchell, A. Peschiulli, N. Lefevre, L.
Meerpoel, B. U. W. Maes, Chem. Eur. J. 2012, 18, 10092–10142; for
selected examples see: b) S. J. Pastine, K. M. McQuaid, D. Sames, J.
Am. Chem. Soc. 2005, 127, 12180–12181; c) C. Zhang, C. Kanta De,
R. Mal, D. Seidel, J. Am. Chem. Soc. 2008, 130, 416–417; d) S. Mur-
arka, C. Zhang, M. D. Konieczynska, D. Seidel, Org. Lett. 2009, 11,
129–132; e) C. Zhang, S. Murarka, D. Seidel, J. Org. Chem. 2009,
74, 419–422; f) M. C. Haibach, I. Deb, C. Kanta De, D. Seidel, J.
Am. Chem. Soc. 2011, 133, 2100–2103; g) K. Mori, S. Sueoka, T.
Akiyama, J. Am. Chem. Soc. 2011, 133, 2424–2426; h) P. A. Vadola,
I. Carrera, D. Sames, J. Org. Chem. 2012, 77, 6689–6702; i) Y.-P. He,
H. Wu, D.-F. Chen, J. Yu, L.-Z. Gong, Chem. Eur. J. 2013, 19, 5232–
5237; j) I. D. Jurberg, B. Peng, E. Wçstefeld, M. Wasserloos, N. Mau-
lide, Angew. Chem. 2012, 124, 1986–1989; Angew. Chem. Int. Ed.
2012, 51, 1950–1953; k) D.-F. Chen, Z.-Y. Han, Y.-P. He, J. Yu, L.-Z.
Gong, Angew. Chem. 2012, 124, 12473–12476; Angew. Chem. Int.
Ed. 2012, 51, 12307–12310; l) L. Zhang, L. Chen, J. Lv, J.-P. Cheng,
S. Luo, Chem. Asian J. 2012, 7, 2569–2576.
[10] a) B. I. Roman, N. De Kimpe, C. V. Stevens, Chem. Rev. 2010, 110,
5914–5988; b) C. C. Malakar, B. U. W. Maes, K. Abbaspour Tehrani,
Adv. Synth. Catal. 2012, 354, 3461–3467.
[11] a) S. Stas, K. Abbaspour Tehrani, Tetrahedron 2007, 63, 8921–8931;
b) K. K. Nanda, B. W. Trotter, Tetrahedron Lett. 2005, 46, 2025–
2028; c) C. Catmela, J. I. Garcꢃa, J. A. Mayoral, L. Salvatella, Can. J.
Chem. 1994, 72, 308–311; d) H. C. Brown, E. J. Mead, C. J. Shoaf, J.
Am. Chem. Soc. 1956, 78, 3613–3614; e) D. Vuluga, J. Legros, B.
Crousse, A. M. Z. Slawin, C. Laurence, P. Nicolet, D. Bonnet-
Delpon, J. Org. Chem. 2011, 76, 1126–1133.
[4] a) C.-Y. Zhou, S.-F. Zhu, L.-X. Wang, Q.-L. Zhou, J. Am. Chem.
Soc. 2010, 132, 10955–10957; b) A. Barchuk, M.-Y. Ngai, M. J. Kri-
sche, J. Am. Chem. Soc. 2007, 129, 8432–8433; c) E. Skucas, J. R.
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
7
&
ÞÞ
These are not the final page numbers!

K. Abbaspour Tehrani et al.
[12] a) M. H. El-Badri, D. Willenbring, D. J. Tantillo, J. Gervay-Hague, J.
Org. Chem. 2007, 72, 4663–4672; b) E. M. Simmons, J. F. Hartwig,
Angew. Chem. 2012, 124, 3120–3126; Angew. Chem. Int. Ed. 2012,
51, 3066–3072.
Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian,
Inc., Wallingford CT, 2009.
[14] a) Y. Ma, E. Lobkovsky, D. B. Collum, J. Org. Chem. 2005, 70,
2335–2337; b) K. B. Aubrecht, M. D. Winemiller, D. B. Collum, J.
Am. Chem. Soc. 2000, 122, 11084–11089; c) J. E. Davies, P. R. Raith-
by, R. Snaith, A. E. H. Wheatley, Chem. Commun. 1997, 1797–1798.
[15] a) B.-A. Feit, S. Shapira, A. Herbst, Tetrahedron 1995, 51, 317–328;
b) R. Withnall, I. R. Dunkin, R. Snaith, J. Chem. Soc. Perkin Trans.
2 1994, 1973–1977; c) M. Majewski, Tetrahedron Lett. 1988, 29,
4057–4060.
[16] C. Reichardt, in Solvents and Solvent Effects in Organic Chemistry,
2nd ed., Wiley-VCH, Weinheim, 1990.
[17] a) S. Searles, Y. L. Nassim, M.-T. R. Lopes, P. T. Tran, P. Crabbꢁ, J.
Chem. Soc. Perkin Trans. 1 1984, 747–751; b) J. Kuang, S. Ma, J.
Org. Chem. 2009, 74, 1763–1765; c) H. Nakamura, T. Kamakura, M.
Ishiku, J.-F. Biellmann, J. Am. Chem. Soc. 2004, 126, 5958–5959.
[13] Gaussian 09, Revision A.2, M. J. Frisch, G. W. Trucks, H. B. Schlegel,
G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V.
Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X.
Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Son-
nenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa,
M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven,
J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J.
Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J.
Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar,
J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W.
Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A.
Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, ꢆ.
Received: February 5, 2013
Published online: && &&, 0000
&
8
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Vinyl-Transfer Reaction
FULL PAPER
Vinylation
C. C. Malakar, S. Stas, W. Herrebout,
K. Abbaspour Tehrani* . .. .. &&&& — &&&&
Lewis Acid Mediated Vinyl-Transfer
Reaction of Alkynes to N-Alkylimines
by Using the N-Alkyl Residue as a
Sacrificial Hydrogen Donor
Vinylation records: A variety of N-
alkyl-a,a-dichloroaldimines can be
vinylated by terminal acetylenes in the
presence of Lewis acids such as In-
reaction leads to geometrically pure
allylic b,b-dichloroamines (see
scheme). Terminal alkynes were used
as a source of vinyl residue, and the N-
alkyl moiety of the imine acts as a sac-
rificial hydrogen donor.
ACHTUNGTRENNUNG
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
9
&
ÞÞ
These are not the final page numbers!